Pseudoxanthoma elasticum: Significance of limited phenotypic expression in parents of affected offspring

doi:10.1067/mjd.2001.112401

Journal of the American Academy of Dermatology

Volume 44, Issue 3, March 2001, Pages 534-537

https://doi.org/10.1067/mjd.2001.112401 Get rights and content

Abstract

The inheritance pattern of pseudoxanthoma elasticum (PXE) is controversial. Inheritance patterns are confounded by delayed diagnosis and mild or limited phenotypic expression among certain family members. Because testing for the genetic mutation(s) responsible for PXE is not routine, genetic counseling must be done with caution. We describe 4 families in which one or more children were diagnosed with PXE. Detailed examination of the parents was carried out, including skin biopsy and ophthalmologic examination. In 3 of the 4 families, one parent had limited phenotypic expression, such as ocular findings without skin lesions or very mild skin lesions with no ocular findings. In the other family, one parent had very mild skin and ocular disease. All 4 affected parents had diagnostic skin biopsy findings. In none of the 4 families was the inheritance pattern clear-cut. Although the inheritence pattern of PXE has been debated, clinically significant stigmata of PXE, which are not always readily apparent, can occur in successive generations. Therefore all first-degree relatives of affected patients should receive a full dermatologic examination as well as a funduscopic examination. If even mild typical skin or eye findings are present, then skin biopsy should be performed. (J Am Acad Dermatol 2001;44:534-7.)

Section snippets

Case 1

A 15-year-old boy was diagnosed with PXE at age 14 years. He had characteristic skin lesions on the neck, first noted at age 7, peau d'orange change on funduscopic examination, and a biopsy specimen of lesional skin that revealed calcification and fragmentation of elastic fibers in the mid dermis.

The patient's family, including two brothers aged 5 and 19 years, his 39-year-old father, and 40-year-old mother were subsequently examined. No evidence of PXE was found in the father or two brothers.

Discussion

Hereditary disorders often have a prolonged time lapse between clinical onset and diagnosis. However, the delay in diagnosis of PXE is unusually long, averaging about 9 years.⁸ This makes early intervention difficult. The disease is often not diagnosed until the fourth or fifth decade of life because the clinical manifestations and complications have not become noticeable or severe enough to warrant medical attention. In addition, further delay occurs because few physicians have been adequately

Acknowledgements

We thank Wayne Fuchs, MD, and Lloyd Wilcox, MD, for their assistance in ophthalmologic evaluation of case 1; Sharon Terry, PXE International, Inc, for providing assistance with patient and family contacts; and Dianne Abuelo, MD, for helpful suggestions.

References (14)

AN Sapadin et al.
Periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks: apparent regression with hemodialysis
J Am Acad Dermatol
(1998)
F Navarro-Lopez et al.
Restrictive cardiomyopathy in pseudoxanthoma elasticum
Chest
(1980)
J Uitto et al.
International Centennial Meeting of Pseudoxanthoma Elasticum: progress in PXE research
J Invest Dermatol
(1998)
M Ekim et al.
Pseudoxanthom elasticum: a rare cause of hypertension in children
Pediatr Nephrol
(1998)
RB. Dymock
Pseudoxanthoma elasticum: report of a case with reno-vascular hypertension
Aust J Dermatol
(1979)
L Schachner et al.
Pseudoxanthoma elasticum with severe cardiovascular disease in a child
Am J Dis Child
(1974)
GL Darmstadt et al.
Disease of the dermis

There are more references available in the full text version of this article.

Cited by (53)

Hypophosphatemic osteosclerosis, hyperostosis, and enthesopathy associated with novel homozygous mutations of DMP1 encoding dentin matrix protein 1 and SPP1 encoding osteopontin: The first digenic SIBLING protein osteopathy?
2020, Bone
Citation Excerpt :
PXE causes calcification of elastic fibers in skin, retina, and arteries [3,32,33]. Some heterozygous defects of ABCC6 lead to limited manifestations of PXE (Forme Fruste, OMIM # 177850) [3,34–36] including vascular calcification. Homozygous or compound heterozygous missense mutations near Patient 1's heterozygous ABCC6 variant (e.g. Trp256Arg) have been reported in PXE.
The SIBLINGs are a subfamily of the secreted calcium-binding phosphoproteins and comprise five small integrin-binding ligand N-linked glycoproteins [dentin matrix protein-1 (DMP1), secreted phosphoprotein-1 (SPP1) also called osteopontin (OPN), integrin-binding sialoprotein (IBSP) also called bone sialoprotein (BSP), matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP)]. Each SIBLING has at least one “acidic, serine- and aspartic acid-rich motif” (ASARM) and multiple Ser-x-Glu/pSer sequences that when phosphorylated promote binding of the protein to hydroxyapatite for regulation of biomineralization. Mendelian disorders from loss-of-function mutation(s) of the genes that encode the SIBLINGs thus far involve DSPP causing various autosomal dominant dysplasias of dentin but without skeletal disease, and DMP1 causing autosomal recessive hypophosphatemic rickets, type 1 (ARHR1). No diseases have been reported from gain-of-function mutation(s) of DSPP or DMP1 or from alterations of SPP1, IBSP, or MEPE.
Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India. Both shared novel homozygous mutations within two genes that encode a SIBLING protein: stop-gain (“nonsense”) DMP1 (c.556G>T,p.Glu186Ter) and missense SPP1 (c.769C>T,p.Leu266Phe). The man alone also carried novel heterozygous missense variants within two additional genes that condition mineral homeostasis and are the basis for autosomal recessive disorders: CYP27B1 underlying vitamin D dependent rickets, type 1, and ABCC6 underlying both generalized arterial calcification of infancy, type 2 and pseudoxanthoma elasticum (PXE). By immunochemistry, his bone contained high amounts of OPN, particularly striking surrounding osteocytes. We review how our patients' disorder may represent the first digenic SIBLING protein osteopathy.
Efficiency of Exome Sequencing for the Molecular Diagnosis of Pseudoxanthoma Elasticum
2015, Journal of Investigative Dermatology
The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exomes with insufficient reads (≤ 20 depth) for the four genes and patients with single mutations were further evaluated by Sanger sequencing (SS), but no additional mutations were found. The potential of WES compared with targeted NGS is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.
Genetics of neurocutaneous disorders. basic principles of inheritance as they apply to neurocutaneous syndromes.
2015, Handbook of Clinical Neurology
Citation Excerpt :
Carriers of one mutation are typically asymptomatic. It is possible that carriers of an ABCC6 mutation may have mild ocular and cutaneous findings, but this is currently under debate in the literature (Bacchelli et al., 1999; Sherer et al., 2001; Martin et al., 2008). Of note, an increased risk for PXE is seen in a few populations including the Afrikaners in South Africa, who display a founder effect, defined as reduced genetic variation in an isolated population descending from a small group of ancestors (Le Saux et al., 2002).
Neurocutaneous disorders vary widely in clinical presentation as well as genetic cause and inheritance pattern. Recent advancements in genetic research have identified many of the causal genes for neurocutaneous disorders, allowing families to receive genetic testing and genetic counseling to better understand carrier risks, recurrence risks for future generations, and reproductive options such as prenatal testing and preimplantation diagnosis. Examples of specific neurocutaneous disorders are utilized to illustrate the various inheritance patterns seen in this heterogeneous group of disorders, including autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, de novo, and somatic and germline mosaicism.
Heritable Diseases Affecting the Elastic Fibers: Cutis Laxa, Pseudoxanthoma Elasticum, and Related Disorders
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Hurwitz Clinical Pediatric Dermatology, Fouth Edition
2011, Hurwitz Clinical Pediatric Dermatology, Fouth Edition
Disorders of elastic tissue
2009, Weedon's Skin Pathology: Third Edition

View all citing articles on Scopus

^☆: Reprint requests: Daniel W. Sherer, MD, The Mount Sinai Medical Center, Department of Dermatology, 5 E 98th St, 6th Floor, Box 1048, New York, NY 10029-6574.

View full text

Pseudoxanthoma elasticum: Significance of limited phenotypic expression in parents of affected offspring☆

Abstract

Section snippets

Case 1

Discussion

Acknowledgements

J Am Acad Dermatol

Chest

J Invest Dermatol

Pseudoxanthom elasticum: a rare cause of hypertension in children

Pediatr Nephrol

Pseudoxanthoma elasticum: report of a case with reno-vascular hypertension

Aust J Dermatol

Pseudoxanthoma elasticum with severe cardiovascular disease in a child

Am J Dis Child

Disease of the dermis